Bone densifying agent characterized by use of cathepsin K inhibitor with PTH

ABSTRACT

The present invention relates to an agent for increasing BMD characterized by use of a cathepsin K inhibitor as a bone resorption inhibitor in combination with a type of PTH as a bone formation stimulator. This agent for increasing BMD is useful for the treatment of osteoporosis, bone fracture, arthritis, rheumatoid arthritis, osteoarthritis, hypercalcemia, osteometastasis of carcinoma, periodontal disease, bone Paget&#39;s disease and other bone metabolic diseases. For example, as the cathepsin K inhibitor, there can be mentioned a compound of formula (W) and a salt thereof, etc.

TECHNICAL FIELD

The present invention relates to an agent for increasing bone mineraldensity (BMD) comprising a cathepsin K inhibitor and a type ofparathyroid hormone (PTH) as active ingredients.

More specifically, the present invention relates to a treating and/orpreventive agent for bone metabolic diseases comprising a cathepsin Kinhibitor and a type of PTH as active ingredients.

BACKGROUND ART

Cathepsin K is a kind of cysteine protease and it belongs to papainsuperfamily. Cathepsin K is specifically recognized in osteoclast and ithas a decomposing activity against bone substrate [J. Biol. Chem., 271,12517 (1996)], so it is expected that cathepsin K inhibitor shows aneffect as a bone resorption inhibitor, against osteoporosis, bonefracture, arthritis, rheumatoid arthritis, osteoarthritis,hypercalcemia, osteometastasis of carcinoma, periodontal disease, bonePaget's disease and other bone-metabolic diseases, in which pathologicalbone resorption is recognized.

On the other hand, PTH (also called parathyroid hormone or parathormone)is a hormone which is assumed to be produced in the chief cells ofparathyroid, and it increases blood calcium concentration and iscontrolled by the phosphorus level.

It is known that PTH shows a stimulating effect on bone formation byintermittant administration and that it increases BMD. Since PTH has astimulating effect on bone formation, unlike in the case of existingdrugs consisting mainly of bone resorption inhibitors, PTH is expectedto be a new type of a drug for osteoporosis.

Osteoporosis is classified in two types of pathologies; primaryosteoporosis and secondary osteoporosis. Primary osteoporosis consistsmainly of postmenopausal osteoporosis and senile osteoporosis and thelike. Secondary osteoporosis consists mainly of diabetic osteoporosisand steroidal osteoporosis and the like.

Both menopausal osteoporosis and senile osteoporosis show thepathologies which is disorder of bone turnover caused by inbalance ofbone resorption and bone formation. Therefore, in the treatment ofosteoporosis, bone resorption inhibitors and bone formation stimulatorsare effective and the bone turnover balance may be improved by thecombining them effectively.

Examples of bone resorption inhibitors include, bisphosphonates (saltsof bisphosphonic acid, abbreviated as BP hereafter), calciumformulations, estrogen receptor modulators, androgen receptor modulator,calcitonin formulations, α-calcitonin gene-related peptide formulations,ipriflavone formulations, anabolic steroid formulations, anti-RANKL(receptor activator of NF-kappa B ligand) antibody and the like; on theother hand, examples of the bone formation stimulators include, types ofPTH PTHrP (parathyroid hormone related protein), BMP (bone morphogeneticprotein), prostaglandin receptor agonists (EP2 agonists, EP4 agonistsand the like), CaR (calcium sensing receptors) antagonist, GSK (glycogensynthase kinase) inhibitors and the like.

Also, for the treatment and/or prevention of bone metabolic diseases,the followings are also used; vitamin D and its derivatives, vitamin Kand its derivatives, strontium formulations, HMG-CoA reductaseinhibitors, steroidal drugs, caspase-1 inhibitors, prostaglandinreceptor antagonists, farnesoid X receptor agonists, progesteroneagonists, anti TN-α antibody, anti-IL-6 antibody, female hormoneformulations, antiinflammatory drugs, metalloprotease inhibitors, andthe like.

Although BP, which is used for the treatment of osteoporosis, has a boneresorption inhibiting effect, it is acknowledged as a problem that itsuppresses bone formation (Osteoporosis Japan, 7(2), 11-16 (1999), Bone,23(4), 333-342 (1998)).

Since bone metabolic diseases are often chronic diseases, the treatmentthereof is often carried out for a long term. Therefore, it has beenconsidered to use several drugs in combination for the improvement ofpatients' compliance and the therapeutic effect.

For example, an effect on increasing bone mineral density is to be moreexpected by combination use of bone formation stimulators and boneresorption inhibitors, but it is clinically demonstrated thatalendronate sodium hydrate (BP), one of bone resorption inhibitors, doesnot show an effect in combination with PTH (a bone formation stimulator)(see The New England Journal of Medicine, 349, 13, 1207-1215 (2003); TheNew England Journal of Medicine, 349, 13, 1216-1226 (2003)).

On the other hand, cathepsin K inhibitors are known as the drugs whichhave a bone resorption inhibiting effect. Cathepsin K inhibitors, unlikeBP, do not inhibit simian bone formation (see Journal of Bone andMineral Research, 16, 10, 1739-1746 (2001)).

The mechanism of bone metabolic diseases is poorly understood and it isnot fully revealed which combination is best for clinically.

As to the treatment of osteoporosis, it is disclosed that a compositioncomprising a cathepsin K inhibitor and other agents (BP, an estrogenreceptor modulator, an androgen receptor modulator, PTH, PTHrP, anosteoclast proton-ATPase inhibitor, an HMG-CoA reductase inhibitor, anα_(v)β₃ receptor antagonist, a p38 kinase inhibitor, growth hormone, anEP₂ agonist, a TNF-α inhibitor, a P2X7 receptor agonist, a matrixmetalloproteinase inhibitor, a VEGF inhibitor and the like) is usefulfor the diseases of osteoporosis, osteoarthritis, osteometastasis ofcarcinoma (see WO03/039534).

On the other hand, it is disclosed that a compound of formula (W)

wherein all symbols have the same meaning as described in thespecification of WO03/091202, has an inhibitory activity againstcathepsin K and that it is useful for the treatment and/or prevention ofbone diseases (see WO03/091202).

However, in these literatures, there is no evidence nor implication whatkind of effect would be given by actually using a cathepsin K inhibitorand PTH in combination.

DISCLOSURE OF THE INVENTION

In the treatment of bone metabolic diseases such as osteoporosis and thelike, a preferable combination of the drugs for the treatment has beenhoped for.

Means of Solving the Problems

As a result of energetic studies considering the above circumstances,the present inventors have found that use of a cathepsin K inhibitor (abone resorption inhibitor), especially the compound of formula (W) asdescribed hereafter, in combination with a type of PTH, especially humanPTH (1-34) (a bone formation stimulator), surprisingly, shows moreexcellent effect in increasing BMD than use of BP (bisphosphonate) (alsoa bone resorption inhibitor) in combination with PTH, and as a result,these combination is by far more excellent, finally to complete thepresent invention.

That is, the present invention relates to an agent for increasing BMDcomprising a cathepsin K inhibitor and one or more PTH(s).

More specifically, the present invention relates to a treating and/orpreventing agent of osteoporosis, bone fracture, arthritis, rheumatoidarthritis, osteoarthritis, hypercalcemia, osteometastasis of carcinoma,periodontal disease, bone Paget's disease and other bone metabolicdiseases, comprising a cathepsin K inhibitor and one or more PTH(s).

Much more specifically, the present invention relates to,

-   [1] an agent for increasing bone mineral density (BMD), comprising a    cathepsin K inhibitor and a type of PTH,-   [2] the agent for increasing BMD according to the above [1], which    is an agent for treating and/or preventing a bone metabolic disease,-   [3] the agent for increasing BMD according to the above [1], wherein    the cathepsin K inhibitor is a compound of formula (W)

wherein R is (1) hydrogen atom, (2) CycA, (3) C1-8 alkyl which may besubstituted with 1 to 5 of substituent(s) selected from halogen, CycA,nitro, trifluoromethyl and cyano,

wherein CycA is a C3-15 mono-, bi- or tri-cyclic carbocyclic ring, or a3- to 15-membered mono-, bi- or tri-cyclic heterocyclic ring comprising1 to 4 of nitrogen atom(s), 1 to 2 of oxygen atom(s) and/or 1 to 2 ofsulfur atom(s),

R¹⁶ is (1) C1-8 alkyl, (2) C2-8 alkenyl, (3) C2-8 alkynyl, (4) CycA, or(5) C1-8 alkyl, C2-8 alkenyl, or C2-8 alkynyl substituted with 1 to 5 ofgroup(s) selected from halogen, nitro, trifluoromethyl, cyano, CycA,—NR¹⁸R¹⁹, —OR¹⁸, —SR¹⁸, —NHC(O)— CycA and —NHC(O)O—(C1-8 alkyl),

R¹⁷, R¹⁸ and R¹⁹ are each independently, hydrogen atom, C1-4 alkyl, CycAor C1-4 alkyl substituted with CycA,

AA¹ is (1) a bond, or

wherein R¹ and R² are each independently, (i) hydrogen atom, (ii) C1-8alkyl, (iii) CycA, or (iv) C1-8 alkyl substituted with 1 to 5 ofgroup(s) selected from the following (a) to (j):

(a) —NR²¹R²², (b) —OR²³, (c) —SR²³, (d) —COR²⁴, (e) —NR²⁵C(O)NR²¹R²²,(f) guanidino, (g) amidino, (h) CycA, and (j) —NR²⁵SO₂R²¹, or

R¹ and R² are taken together to form, C2-8 alkylene (in which one carbonatom in the alkylene may be replaced by oxygen atom, sulfur atom or—NR²⁰—, and the alkylene may be substituted with —NR²¹R²², —OR²³ oroxo),

wherein R²⁰ is hydrogen atom, C1-4 alkyl, —C(O)O(C1-4 alkyl), CycA, orC1-4 alkyl substituted with CycA,

R²¹, R²², R²³ and R²⁵ are each independently, hydrogen atom, C1-4 alkyl,CycA, or C1-4 alkyl substituted with CycA,

R²⁴ is C1-4 alkyl, CycA, —NR²¹R²², —OR²³, —SR²³, or C1-4 alkylsubstituted with CycA,

R³ is hydrogen atom, C1-8 alkyl, CycA, or C1-8 alkyl substituted withCycA, or

R³ is taken together with R¹ to form C2-6 alkylene (in which one carbonatom in the alkylene may be replaced by oxygen atom, sulfur atom or—NR²⁰—, and the alkylene may be substituted with —NR²¹R²², —OR²³, —SR²³or oxo), or

R and AA¹ may be taken together to form

wherein CycB is a 5- to 12-membered mono- or bi-cyclic heterocyclic ringand the other symbols have the same meanings as hereinbefore,

AA² is (1) a bond,

wherein R⁴ and R⁵ are each independently, (i) hydrogen atom, (ii) C1-8alkyl, (iii) CycA or (iv) C1-8 alkyl substituted with 1 to 5 of group(s)selected from the following (a) to (j):

(a) —NR³¹R³², (b) —OR³³, (c) —SR³³, (d) —COR³⁴, (e) —NR³⁵C(O)NR³¹R³²,(f) guanidino, (g) amidino, (h) CycA and (j) —NR³⁵SO₂R³¹, or

R⁴ and R⁵ may be taken together to form C2-8 alkylene (one carbon atomin the alkylene chain may be replaced by oxygen atom, sulfur atom or—NR³⁰—, and the alkylene may be substituted with —NR³¹R³², —OR³³, —SR³³,or oxo),

wherein R³⁰ is hydrogen atom, C1-4 alkyl, —C(O)O(C1-4 alkyl), CycA, orC1-4 alkyl substituted with CycA,

R³¹, R³², R³³ and R³⁵ are each independently, hydrogen atom, C1-4 alkyl,CycA or C1-4 alkyl substituted with CycA,

R³⁴ is C1-4 alkyl, CycA, —NR³¹R³², —OR³³, —SR³³, or C1-4 alkylsubstituted with CycA,

R⁶ is hydrogen atom, C1-8 alkyl, CycA, or C1-8 alkyl substituted withCycA, or

R⁶ is taken together with R⁴ or R to form a C2-6 alkylene (one carbonatom in the alkylene chain may be replaced by oxygen atom, sulfur atomor —NR³⁰—, and the alkylene may be replaced by —NR³¹R³², OR³³, SR³³, oroxo),

R³⁸ is hydrogen atom, C1-4 alkyl, CycA, or C1-4 alkyl substituted CycA,or when AA¹ is a bond, R³⁸ may be taken together with R to form C2-6alkylene (one carbon atom in the alkylene may be substituted with oxygenatom, sulfur atom or —NR³⁷—,

wherein R³⁷ is hydrogen atom or C1-4 alkyl,

CycC is a 3- to 17-membered mono- or bi-cyclic heterocyclic ring,

CycD is a C3-14 mono- or bi-cyclic carbocyclic ring or a 3- to14-membered mono- or bi-cyclic heterocyclic ring, or

AA² may be taken together with AA¹ to form

wherein CycE is a 4- to 18-membered mono- or bi-cyclic heterocyclicring, CycF is a 5- to 8-membered mono-cyclic heterocyclic ring, and theother symbols have the same meanings as described hereinbefore,

R⁷ and R⁸ are each independently, (1) hydrogen atom, (2) C1-8 alkyl, (3)CycA, or (4) C1-8 alkyl substituted with 1 to 5 of group(s) selectedfrom the following (i) to (x):

(i) —NR⁴¹R⁴², (ii) —OR⁴³, (iii) —SR⁴³, (iv) —COR⁴⁴, (v)—NR⁴⁵C(O)NR⁴¹R⁴², (vi) guanidino, (vii) amidino, (viii) CycA, (ix)—NR⁴⁵SO₂R⁴¹ and (x) —P(O)(OR⁴⁶)(OR⁴⁷), or

R⁷ and R⁸ may be taken together to form C2-8 alkylene (one carbon atomin the alkylene chain may be replaced by oxygen atom, sulfur atom or—NR⁴⁰—, and the alkylene may be substituted with —NR⁴¹OR⁴², —OR⁴³, —SR⁴³or oxo),

R⁴⁰ is hydrogen atom, C1-4 alkyl, —C(O)O(C1-4 alkyl), CycA, or C1-4alkyl substituted with CycA,

R⁴¹, R⁴², R⁴³ and R⁴⁵ are each independently, hydrogen atom, C1-4 alkyl,CycA, or C1-4 alkyl substituted with CycA,

R⁴⁴ is C1-4 alkyl, CycA, —NR⁴¹R⁴², —OR⁴³, —SR⁴³, or C1-4 alkylsubstituted with CycA,

R⁴⁶ and R⁴⁷ are each independently, hydrogen atom or C1-8 alkyl,

R⁹ is hydrogen atom, C1-8 alkyl, CycA, or C1-8 alkyl substituted withCycA, or

R⁹ may be taken together with R⁷ or R to form C2-6 alkylene (one carbonatom in the alkylene chain may be replaced by oxygen atom, sulfur atomor —NR⁴⁰—, and the alkylene may be substituted with —NR⁴¹R⁴², —OR⁴³,—SR⁴³, or oxo, wherein all symbols have the same meanings as describedhereinbefore),

is a group represented by the following (1), (2) or (3):

wherein R^(A1) and R^(A2) are each independently, (i) hydrogen atom,(ii) C1-8 alkyl, (iii) C2-8 alkenyl, (iv) —NR^(Z1)R^(Z2), (v) —OR^(Z3),(vi) —SR^(Z3), (vii) —COR^(Z4), (viii) CycP, (ix) C1-8 alkyl or C2-8alkenyl substituted with 1 to 5 of group(s) selected from CycP,—NR^(Z1)R^(Z2), —OR^(Z3), —SR^(Z3), —COR^(Z4), —SO₂R^(Z4), —COOR^(Z3),—CONR^(Z1)R^(Z2), —SO₂NR^(Z1)R^(Z2) and —P(O)(OR^(Z5))(OR^(Z6)),

wherein R^(Z1) and R^(Z2) are each independently, hydrogen atom, C1-8alkyl, C2-8 alkenyl, CycP, C2-8 acyl, or C1-8 alkyl substituted withCycP, C2-8 acyl, C1-8 alkoxy, C1-8 alkylthio, mono(C1-8 alkyl)amino ordi(C1-8 alkyl)amino,

R^(Z3) is hydrogen atom, C1-8 alkyl, C2-8 alkenyl, CycP, or C1-8 alkylsubstituted with 1 to 5 of group(s) selected from CycP, C1-8 alkoxy,C1-8 alkylthio, amino, mono(C1-8 alkyl)amino, di(C1-8 alkyl)amino andC2-8 acyl,

R^(Z4) is C1-8 alkyl, CycP, or C1-8 alkyl substituted with 1 to 5 ofgroup(s) selected from CycP, C1-8 alkoxy, C1-8 alkylthio, mono(C1-8alkyl)amino, di(C1-8 alkyl)amino and C2-8 acyl,

R^(Z5) and R^(Z6) are each independently, hydrogen atom or C1-8 alkyl,

CycP is a C4-10 carbocyclic ring or a 5- to 10-membered heterocyclicring comprising 1 to 4 of nitrogen atom(s), 1 to 2 of oxygen atom(s)and/or 1 to 2 of sulfur atom(s), and R¹⁰ has the same meaning asdescribed hereinbefore, or

R^(A1) and R^(A2) may be taken together with the adjacent carbon atom toform CycH

wherein CycH is a C4-10 mono- or bi-cyclic carbocyclic ring or a 4- to10-membered mono- or bi-cyclic heterocyclic ring and R¹⁰ has the samemeaning as described hereinbefore,

R^(A1) and R¹⁰ may be taken together with the adjacent carbon atom andnitrogen atom to form

wherein CycJ is a 5- to 10-membered mono- or bi-cyclic heterocyclicring, R^(A2) has the same meaning as described hereinbefore,

wherein R^(A3) is (i) C1-8 alkyl, (ii) C2-8 alkenyl, (iii)NR^(Z1)R^(Z2), (ix) —OR^(Z3), (v) —SR^(Z3), (vi) —COR^(Z4), (vii) CycP,or (viii) C1-8 alkyl or C2-8 alkenyl substituted with 1 to 5 of group(s)selected from —NR^(Z1)R^(Z2), —OR^(Z3), —SR^(Z3), —COR^(Z4), —SO₂R^(Z4),CycP and —P(O)(OR^(Z5))(OR^(Z6)), wherein all symbols have the samemeanings as described hereinbefore,

R^(A4) is (i) hydrogen atom, (ii) C1-8 alkyl, (iii) C2-8 alkenyl, (iv)—COR^(Z4), (v) CycP, or (vi) C1-8 alkyl, or C2-8 alkenyl substitutedwith 1 to 5 of group(s) selected from CycP, —NR^(Z1)R^(Z2), —OR^(Z3),—SR^(Z3), —COR^(Z4), —SO₂R^(Z4), —COOR^(Z3), —CONR^(Z1)R^(Z2),—SO₂NR^(Z1)R^(Z2) and —P(O)(OR^(Z5))(OR^(Z6)), wherein all symbols havethe same meanings as described hereinbefore,

R¹⁰ has the same meaning as described hereinbefore, or

R^(A3) and R^(A4) may be taken together with the adjacent carbon atomand nitrogen atom to form

wherein CycK is a 5- to 10-membered mono- or bi-cyclic heterocyclicring, and R¹⁰ has the same meaning as described hereinbefore, or

R^(A3) and R¹⁰ may be taken together with the adjacent carbon atom andnitrogen atom to form

wherein CycL is a 5- to 10-membered mono- or bi-cyclic heterocyclicring, and R^(A4) has the same meaning as described hereinbefore,

wherein n is an integer of 1 or 2, and the other symbols have the samemeanings as described hereinbefore, R^(A3) and R^(A4) may be takentogether with the adjacent nitrogen atom and sulfur atom to form

wherein CycM is a 5- to 10-membered mono- or bi-cyclic heterocyclicring, and the other symbols have the same meaning as describedhereinbefore, or

R^(A3) and R¹⁰ may be taken together with the adjacent nitrogen atom andsulfur atom to form

wherein CycN is a 5- to 10-membered mono- or bi-cyclic heterocyclicring, and the other symbols have the same meanings as describedhereinbefore,

CycA's, each independently, and CycA, CycB, CycC, CycD, CycE, CycF,CycH, CycJ, CycK, CycL, CycM, CycN and CycP may be each independentlysubstituted with 1 to 5 of R²⁷,

R²⁷ is (1) C1-8 alkyl, (2) halogen, (3) —NR¹¹R¹², (4) —OR¹³, (5) —SR¹³,(6) CycG, (7) nitro, (8) cyano, (9) oxo, (10) —COR⁴, (11) —SO₂R¹⁴, (12)—P(O)(OR¹⁵)(OR¹⁵), (13) guanidino, (14) amidino, or (15) C1-8 alkylsubstituted with 1 to 5 of group(s) selected from the following (i) to(xii);

(i) halogen, (ii) —NR¹¹R¹², (iii) —OR¹³, (iv) —SR¹³, (v) CycG, (vi)nitro, (vii) cyano, (viii) —COR¹⁴, (ix) —SO₂R¹⁴, (x) —P(O)(OR¹⁵)(OR¹⁵),(xi) guanidino, and (xii) amidino,

wherein R¹¹ and R¹² are each independently, hydrogen atom, C1-4 alkyl,C1-4 alkoxy, —C(O)O—(C1-4 alkyl), CycG, or C1-4 alkyl substituted withCycG,

R¹³ is hydrogen atom, C1-4 alkyl, trifluoromethyl, CycG, or C1-4 alkylsubstituted with CycG,

CycGs are each independently, a 4- to 10-membered mono- or bi-cycliccarbocyclic ring, or a 5- to 10-membered mono- or bi-cyclic heterocyclicring comprising 1 to 4 of nitrogen atom(s), 1 to 2 of oxygen atom(s)and/or 1 to 2 of sulfur atom(s),

R¹⁴ is C1-8 alkyl, CycG, —NR¹¹R¹², —OR¹³, —SR¹³, or C1-8 alkylsubstituted with CycG, —NR¹¹R¹², —OR¹³ or —SR¹³,

R¹⁵s are, each independently, hydrogen atom or C1-8 alkyl,

when CycH, CycJ, CycK, CycL, CycM or CycN contains a saturated carbonatom, it may form a spiro ring with CycQ at the saturated carbon atom,

wherein CycQ is a C3-10 saturated or partially unsaturated mono-cycliccarbocyclic ring or a 5- to 8-membered saturated or partiallyunsaturated mono-cyclic heterocyclic ring comprising one of —NR^(Q)—,wherein R^(Q) is C1-8 alkyl, C2-8 acyl, —SO₂— (C1-8 alkyl), benzoyl,benzenesulfonyl, or toluenesulfonyl, one of oxygen atom and/or one ofoptionally oxidized sulfur atom, a salt thereof, an N-oxide thereof, asolvate thereof or a prodrug thereof,

-   [4] the agent for increasing BMD according to the above [3], wherein    the compound of formula (W) is-   (1)    N-{3-[(2Z)-2-(3-methyl-1,3-thiazolidin-2-ylidene)hydrazino]-2,3-dioxo-1-tetrahydro-2H-pyran-4-ylpropyl}cycloheptanecarboxamide,-   (2)    N-[(1S)-3-{(2Z)-2-[(4R)-3,4-dimethyl-1,3-thiazolidin-2-ylidene]hydrazino}-2,3-dioxo-1-(tetrahydro-2H-pyran-4-yl)propyl]cycloheptanecarboxamide,-   (3)    N-{(1S)-1-cyclohexyl-3-[(2,5-dioxo-1-pyrrolidinyl)amino]-2,3-dioxopropyl}cycloheptanecarboxamide,-   (4)    N-((1S)-3-{(2Z)-2-[(4S)-3-ethyl-4-methyl-1,3-thiazolidin-2-ylidene]hydrazino}-2,3-dioxo-1-tetrahydro-2H-pyran-4-ylpropyl)cycloheptanecarboxamide,-   (5)    N-((1R)-3-{(2Z)-2-[(4R)-3,4-dimethyl-1,3-thiazolidin-2-ylidene]hydrazino}-2,3-dioxo-1-tetrahydro-2H-pyran-4-ylpropyl)cycloheptanecarboxamide,-   (6)    N-{3,3-dimethyl-1-[[(2Z)-2-(3-methyl-1,3-thiazolidin-2-ylidene)hydrazino](oxo)acetyl]butyl]cyclohexanecarboxamide,-   (7)    N-{3-[(2Z)-2-(3-methyl-1,3-thiazolidin-2-ylidene)hydrazino]-2,3-dioxo-1-tetrahydro-2H-pyran-4-ylpropyl}cyclohexanecarboxamide,-   (8)    N-(3-{(2Z)-2-[(4R)-3,4-dimethyl-1,3-thiazolidin-2-ylidene]hydrazino}-2,3-dioxo-1-tetrahydro-2H-pyran-4-ylpropyl)cycloheptanecarboxamide    or-   (9)    (N-((1S)-3-{(2Z)-2-[(4S)-3,4-dimethyl-1,3-thiazolidin-2-ylidene]hydrazino}-2,3-dioxo-1-tetrahydro-2H-pyran-4-ylpropyl)cycloheptanecarboxamide),-   [5] the agent for increasing BMD according to the above [3], wherein    the compound of formula (W) is-   N-{3-[(2Z)-2-(3-methyl-1,3-thiazolidin-2-ylidene)hydrazino]-2,3-dioxo-1-tetrahydro-2H-pyran-4-ylpropyl}cycloheptanecarboxamide    or-   N-[(1S)-3-{(2Z)-2-[(4R)-3,4-dimethyl-1,3-thiazolidin-2-ylidene]hydrazino}-2,3-dioxo-1-(tetrahydro-2H-pyran-4-yl)propyl]cycloheptanecarboxamide,-   [6] the agent for increasing BMD according to the above [1], wherein    the cathepsin K inhibitor is orally administered and the type of PTH    is parenterally administered,-   [7] the agent for increasing BMD according to the above [3], further    comprising one or more selected from a prostaglandin receptor    agonist, a prostaglandin receptor antagonist, a vitamin D or a    derivative thereof, a calcium formulation, a vitamin K and a    derivative thereof a calcitonin formulation, a strontium    formulation, an estrogen receptor modulator, anti-TNF-α antibody,    anti-IL-6 antibody, an HMG-CoA reductase inhibitor, a female hormone    formulation, an antiinflammatory drug, PTHrP, a bone formation    protein formulation, an androgen receptor modulator, a steroidal    drug, a caspase-1 inhibitor, a farnesoid X receptor agonist, a    progesteron agonist, anti-RANKL antibody, a metalloprotease    inhibitor, a protein assimilation steroidal formulation, a calcium    sensing receptor antagonist and a glycogen synthase kinase    inhibitor.-   [8] the agent for increasing BMD according to the above [2], wherein    the bone metabolic disease is osteoporosis, bone fracture,    arthritis, rheumatoid arthritis, osteoarthritis, hypercalcemia,    osteometastasis of carcinoma, osteosarcoma, periodontal disease    and/or bone Paget's disease,-   [9] the agent for increasing BMD according to the above [1], wherein    the cathepsin K inhibitor is the compound of formula (W) described    in the above [3], a salt thereof, an N-oxide thereof, a solvate    thereof or a prodrug thereof, and a type of PTH is human PTH (1-34),-   [10] the agent for increasing BMD according to the above [9],    wherein the compound of formula (W) is-   N-{3-[(2Z)-2-(3-methyl-1,3-thiazolidin-2-ylidene)hydrazino]-2,3-dioxo-1-tetrahydro-2H-pyran-4-ylpropyl}cycloheptanecarboxamide    or-   N-[(1S)-3-{(2Z)-2-[(4R)-3,4-dimethyl-1,3-thiazolidin-2-ylidene]hydrazino}-2,3-dioxo-1-(tetrahydro-2H-pyran-4-yl)propyl]cycloheptanecarboxamide,-   [11] a method for increasing BMD, comprising administering to a    mammal an effective amount of the compound of formula (W) described    in the above [3], a salt thereof, an N-oxide thereof, a solvate    thereof or a prodrug thereof and a type of PTH, and-   [12] use of the compound of formula (W) described in the above [3],    a salt thereof, an N-oxide thereof, a solvate thereof or a prodrug    thereof and a type of PTH, for the manufacture of an agent for    increasing BMD.

That is, the present invention relates to an agent for increasing BMD,and such an agent for increasing BMD is useful for the treatment and/orprevention of osteoporosis, bone fracture, arthritis, rheumatoidarthritis, osteoarthritis, hypercalcemia, osteometastasis of carcinoma,osteosarcoma, periodontal disease and/or bone Paget's disease and otherbone metabolic diseases.

In the present invention, cathepsin K inhibitors are not limited inparticular, if known in general. The examples include, the compoundsdescribed in the specifications of WO01/40204, WO01/44214, WO01/55118,WO01/55123, WO02/96892, WO03/91202 and the like.

In the present invention, the cathepsin K inhibitor is preferably acompound described in the specification of WO03/091202, i.e. thecompound of formula (W), a salt thereof, an N-oxide thereof, a solvatethereof or a prodrug thereof.

The salts of the compound of formula (W) are pharmaceutically acceptableand low-toxic and water soluble ones are preferable. Examples forappropriate salts include, salts of alkali metals (potassium, sodium,lithium and the like), salts of alkaline earth metals (calcium,magnesium and the like), ammonium salts (tetramethylammonium salt,tetrabutylammonium salt and the like), salts of organic amines(triethylamine, methylamine, dimethylamine, cyclopentylamine,benzylamine, phenethylamine, piperidine, monoethanolamine,diethanolamine, tris(hydroxymethyl)methylamine, lysine, arginine,N-methyl-D-glucamine and the like), acid addition salts [salts ofinorganic acids (hydrochloride, hydrobromide, hydroiodide, sulfate,phosphate, nitrate and the like), salts of organic acids (acetate,trifluoroacetate, lactate, tartrate, oxalate, fumarate, maleate,benzoate, citrate, methanesulfonate, ethanesulfonate, benzenesulfonate,toluenesulfonate, isethionate, glucronate, gluconate and the like) andthe like].

Examples of the N-oxides of the compound of formula (W) include, thosecompounds wherein a nitrogen atom in the compound of formula (W) isoxidized. The N-oxides of the present invention may be further convertedinto the above alkali metal salts, alkaline earth metal salts, ammoniumsalts, organic amine salts, acid addition salts or the like.

Examples of solvates of the compound of formula (W) include, solvates ofwater, alcohols (ethanol, and the like) and the like. The solvates arepreferably non-toxic and water-soluble. Examples of the solvates of thecompound of formula (W) include, solvates of the alkali metal salts,alkaline earth metal salts, the ammonium salts, the organic amine salts,the acid addition salts, the N-oxides and the like.

The compound of formula (W) may be converted into the salts as describedhereinbefore, N-oxides as described hereinbefore, solvates as describedhereinbefore by known methods.

The prodrugs of the compound of formula (W) mean the compounds convertedinto the compound of formula (W) by the reactions of enzymes, gastricacid and the like in an organism. As the prodrugs of the compound offormula (W), when the compound of formula (W) has amino group, the aminogroup of the compound is acylated, alkylated, or phosphorylated, (e.g.the amino group of the compound of formula (W) is eicosanoylated,alanylated, pentylaminocarbonylated,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylated,tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated,acetoxymethylated, tert-butylated and the like); when the compound offormula (W) has hydroxy group, the hydroxy group of the compound isacylated, alkylated, phosphorylated, borated (e.g. the hydroxy group ofthe compound of formula (W) is acetylated, palmitoylated, propanoylated,pivaloylated, succinylated, fumarylated, alanylated,dimethylaminomethylcarbonylated and the like); when the compound offormula (W) has carboxy group, the carboxy group of the compounds isesterified, amidated (e.g., the carboxy group of the compound of formula(W) is ethylesterified, phenylesterified, carboxymethylesterified,dimethylaminomethylesterified, pivaloyloxymethylesterified,ethoxycarbonyloxyethylesterified, phthalidylesterified,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methylesterified,cyclohexyloxycarbonylethylesterified, methylamidated and the like); andthe like. These compounds can be manufactured by the conventionalmethods. In addition, the prodrugs of the compounds of formula (W) maybe solvates or non-solvates. The prodrugs of the compound of formula (W)may be those ones which are converted to a compound of formula (W) inphysiological conditions as described in Molecular Design, as Vol. 7 ofDevelopment of pharmaceutical drugs, 1990. 163-198, Hirokawa Publishing.And the compound of formula (W) may be labeled with isotopes (e.g. ³H,¹⁴C, ³⁵S, ¹²⁵I and the like) and the like.

As the compound of formula (W), those compounds described in thespecification of WO03/091202 are all preferable and more preferably, acompound of formula (W-1)

wherein R^(S) and R^(T) are each independently, hydrogen atom, C1-4alkyl such as methyl, ethyl and the like, a compound of formula (W-2)

wherein all symbols have the same meanings as described hereinbefore, acompound of formula (W-3)

wherein all symbols have the same meanings as described hereinbefore, acompound of formula (W-4)

wherein all symbols have the same meanings as described hereinbefore, acompound of formula (W-5)

wherein R^(T) has the same meaning as described hereinbefore, a compoundof formula (W-6)

wherein R^(T) has the same meaning as described hereinbefore, a compoundof formula (W-7)

wherein R^(T) has the same meaning as described hereinbefore, a compoundof formula (W-8)

wherein R^(T) has the same meaning as described hereinbefore, a compoundof formula (W-9)

wherein R⁷ has the same meaning as R^(T), a compound of formula (W-10)

wherein R^(T) has the same meaning as described hereinbefore, a compoundof formula (W-1-1)

wherein R^(T1) is hydrogen atom or methyl, the symbol

-   -           indicates that the substituent attached thereto is in front of        the sheet (β-position), and the symbol    -           indicates that the substituent attached thereto is behind the        sheet (α-position)), a salt thereof, an N-oxide thereof, a        solvate thereof and a prodrug thereof.

Particularly preferable are,

-   (1)    N-{3-[(2Z)-2-(3-methyl-1,3-thiazolidin-2-ylidene)hydrazino]-2,3-dioxo-1-tetrahydro-2H-pyran-4-ylpropyl}cycloheptanecarboxamide    hydrochloride (compound described in the example 8(52) of the    specification of WO03/091202, hereafter called the compound (I)),-   (2)    N-[(1S)-3-{(2Z)-2-[(4R)-3,4-dimethyl-1,3-thiazolidin-2-ylidene]hydrazino}-2,3-dioxo-1-(tetrahydro-2H-pyran-4-yl)propyl]cycloheptanecarboxamide    (compound described in the example 10(7) of idem),-   (3)    N-{(1S)-1-cyclohexyl-3-[(2,5-dioxo-1-pyrrolidinyl)amino]]-2,3-dioxopropyl}cycloheptanecarboxamide    (compound described in the example 5(14) of idem),-   (4)    N-((1S)-3-{(2Z)-2-[(4S)-3-ethyl-4-methyl-1,3-thiazolidin-2-ylidene]hydrazino}-2,3-dioxo-1-tetrahydro-2H-pyran-4-ylpropyl)cycloheptanecarboxamide    (compound described in the example 10 of idem),-   (5)    N-((1R)-3-{(2Z)-2-[(4R)-3,4-dimethyl-1,3-thiazolidin-2-ylidene]hydrazino}-2,3-dioxo-1-tetrahydro-2H-pyran-4-ylpropyl)cycloheptanecarboxamide    (compound described in the example 10(62) of idem),-   (6)    N-{3,3-dimethyl-1-[[(2Z)-2-(3-methyl-1,3-thiazolidin-2-ylidene)hydrazino](oxo)acetyl]butyl}cyclohexanecarboxamide    hydrochloride (compound described in the examples 8(10) of idem),-   (7)    N-{3-[(2Z)-2-(3-methyl-1,3-thiazolidin-2-ylidene)hydrazino]-2,3-dioxo-1-tetrahydro-2H-pyran-4-ylpropyl}cyclohexanecarboxamide    hydrochloride (compound described in the example 8(24) of idem),-   (8)    N-(3-{(2Z)-2-[(4R)-3,4-dimethyl-1,3-thiazolidin-2-ylidene]hydrazino}-2,3-dioxo-1-tetrahydro-2H-pyran-4-ylpropyl)cycloheptanecarboxamide    (compound described in the example 10(2) of idem) and the like.

And, the enantiomer of the compound (5), i.e. (9)(N-((1S)-3-{(2Z)-2-[(4S)-3,4-dimethyl-1,3-thiazolidin-2-ylidene]hydrazino}-2,3-dioxo-1-tetrahydro-2H-pyran-4-ylpropyl)cycloheptanecarboxamide)is also preferably used.

In addition to the compound (1) to (9), corresponding free compounds,salts thereof, solvates thereof or prodrugs thereof are preferable aswell.

Particularly preferably, (1)N-{3-[(2Z)-2-(3-methyl-1,3-thiazolidin-2-ylidene)hydrazino]-2,3-dioxo-1-tetrahydro-2H-pyran-4-ylpropyl}cycloheptanecarboxamidehydrochloride and (2)N-[(1S)-3-{(2Z)-2-[(4R)-3,4-dimethyl-1,3-thiazolidin-2-ylidene]hydrazino}-2,3-dioxo-1(tetrahydro-2H-pyran-4-yl)propyl]cycloheptanecarboxamide are used.

The compounds of (1) to (8) may be prepared according to the methoddescribed in the specification of WO03/091202. The compound of (9) maybe prepared by subjecting the compound (8) to recrystallization fromisopropylamine and ethyl acetate. Specifically, it may be prepared bythe following example 1.

In the present invention, the dosage of the compound of formula (W)which is used as a cathepsin K inhibitor, depends on age, sex, bodyweight, symptom, race and the like, and it also depends on the conditionof the disease, administration route, the condition of the kidneys andliver of the patient, and the compound to be used and the kind of salt.Those skilled in the art can easily subscribe the required dose in orderto suppress the progress of the symptoms or to treat the disease.

The compound of formula (W) may be administered orally, intravenously,topically such as subcutaneously or into a joint cavity, ortransdermally, and the like. The interval between administrations are,for example, approximately one hour, approximately two hours,approximately 4 hours, approximately 6 hours, approximately 12 hours,approximately 1 day, approximately 2 days, approximately 3 days,approximately 4 days, approximately 1 week, approximately 2 weeks,approximately 1 month, approximately 2 months, approximately 3 months,approximately 4 months, approximately 6 months, approximately 1 year andthe like. Once to four times a day dosing may be carried out.

The compound of formula (W) may be used in various kinds of formulationsaccording to known methods per se, e.g. the methods described in thespecification of WO03/091202 as a pharmaceutical composition.

Cathepsin K inhibitors may be administered as a solid formulation fororal administration, e.g. tablets, pills, dispersants, granules,capsules and the like.

Capsules include, hard capsules and soft capsules.

In these solid agents for oral administration, one active substance ormore may be administered as they are, or may be admixed with dilutingagents (lactose, mannitol, glucose, microcrystalline cellulose, starchand the like), binding agents (hydroxypropylcellulose,polyvinylpyrrolidone, magnesium aluminometasilicate and the like),disintegrating agents (cellulose calcium glycolate and the like),lubricating agents (magnesium stearate and the like), stabilizingagents, dissolution assisting agents (glutamic acid, aspartic acid andthe like) and the like, to be formulated by the conventional methods.And also, if required, they may be coated with one or more of coatingagent (white sugar, gelatin, hydroxypropylcellulose,hydroxypropylmethylcellulose phthalate and the like). The solid agentsalso include capsules made of absorbable substances such as gelatin.

Examples for liquid formulations for oral administration include, forexample, a pharmaceutically acceptable aqueous formulation, suspensions,emulsions, syrups, elixirs and the like. In these liquid formulations,one or more of active substance is diluted in generally used diluents(purified water, ethanol or a mixture thereof and the like). And thisliquid formulation may further include moistening agents, suspendingagents, emulsifying agents, sweetening agents, flavoring agents,aromatic agents, preserving agents, buffering agents and the like.

For example, when the compound of formula (W) is orally administered, asthe formulation, each of a tablet, a pill, a dispersant, a granule and acapsule is preferable. Such formulations may include preferably,approximately 1 to 1,000 mg of a cathepsin K inhibitor, more preferablyapproximately 5 to 300 mg.

In the present invention, examples of the types of PTH include, PTH andPTH analogues.

PTH represents parathyroid hormone (parathormone) and examples of PTHinclude natural types of PTH, recombinant PTHs manufactured by agenetically engineering method, chemically synthesized PTHs, andpreferable examples include, human PTH consisting of 84 amino acidresidues (human PTH (1-84)), especially recombinant human PTH (1-84)manufactured by a genetically engineering method. And examples of thePTH derivatives include, for example, a partial peptide of theabove-mentioned PTH, a peptide wherein the constitutive amino acid ofPTH itself or its partial peptide is replaced by other amino acids ordeleted, or added with one or more of amino acid and the like, all ofwhich have an analogous activity as PTH. Examples of the partialpeptides of PTH include, human PTH (1-34), human PTH (1-64), human PTH(35-84), bovine PTH (1-34) and the like. PTH (1-34) represents human PTH(human PTH (1-34), human PTH (1-34) amide and the like) consisting of 34amino acid residue from N-terminus to 34th amino acid, particularlyrecombinant human PTH (1-34) (e.g. CHS13340, which has been developed asan intranasal formulation) which was manufactured by a geneticallyengineering method.

One kind of PTH may be solely used or several types of PTH may be usedin combination.

Preferable examples of the amino acid replacement include, thereplacement of constitutive amino acid at the 8-position by leucine ornorleucine, at the 18-position by leucine or norleucine, at the34-position by tyrosine and the like.

In the present invention, the purity of the type of PTH is notnecessarily 100%, but substantially pure types of PTH are alsoacceptable. {Substantially pure} means that the PTH is purified to showa single peak in the HPLC, and preferably, it means that the PTH isconfirmed to be single by the techniques of SDS-PAGE, capillaryelectrophoresis or the like. Such types of PTH may be prepared orconfirmed by the method described in JP6-87897(A), JP4-505259(T), J.Biol. Chem., 265, 17854 (1990), or by the method improved thosedescribed in the literature.

Types of PTH are preferably administered parenterally, and morepreferably intravenously, by topical injections such as subcutaneousinjections or injections in the joint cavity, transdermally,intranasally, and the like, more preferable are subcutaneous injectionand intranasal administration. Types of PTH are preferably administeredintermittently. Intermittent administration is carried out at theinterval of, for example, approximately 1 hour, approximately 2 hours,approximately 4 hours, approximately 6 hours, approximately 12 hours,approximately 1 day, approximately 2 days, approximately 3 days,approximately 4 days, approximately 1 week, approximately 2 weeks,approximately 1 month, approximately 2 months, approximately 3 months,approximately 4 months, approximately 6 months, approximately 1 year andthe like.

In the present invention, the dosages of types of PTH depend on thediseases, symptom, severity, conditions of the diseases, administrationroute, conditions of kidneys and liver of the patient, the compound orthe salt and the like, but those skilled in the art can prescribe thenecessary amount for dosage in order to suppress the progress ofsymptoms or to treat the disease. In systemical administration,approximately 1 μg to 1000 μg per kg (body weight) is preferable andmore preferable is 5 μg to 200 μg per kg (body weight).

In the present invention, the additives used in the pharmaceuticalcompositions are selected from diluting agents, binding agents,moistening agents, stabilizing agents or the like.

In the present invention, when the cathepsin K inhibitors and/or thetypes of PTH are used as an injection, they may be dissolved, suspendedor emulsified in a medium.

Examples of the medium include, distilled water for injection,physiological saline, vegetable oil, propylene glycol, polyethyleneglycol, alcohols such as ethanol and the like and the combinationthereof.

And the injections may further include, stabilizing agents such assodium citrate, sodium edetate and the like; solubilizing agents such asglutamic acid, aspartic acid, polysorbate80® and the like; suspendingagents such as surfactants (stearyl triethanolamine, sodium laurylsulfate, lauryl aminopropionate, lecithin, benzalkonium chloride,benzetonium chloride, glyceryl monostearate, polyoxyethylenehydrogenated castor oil, polysorbate, and the like), polyvalent alcohol(glycerin, macrogol and the like), saccharides (sorbitol, mannitol,sucrose, and the like), celluloses (methyl cellulose, carboxymethylcellulose, hydroxypropylmethyl cellulose and the like), hydrophilicmacromolecules (polyvinylalcohol, polyvinylpyrrolidone, carboxyvinylpolymer, sodium carboxymethyl cellulose, methyl cellulose, chondroitinsulfate and the like), emulsifying agents such as glycerin esters,saponin (sophora saponin, quillai extract, soybean saponin, and thelike), sucrose fatty acid ester (sucrose ester and the like), lecithin(vegetable lecithin, egg-york lecithin, soybean lecithin, and the like),and the like; soothing agents such as benzylalcohol, chlorobutanol,propyleneglycol, ethyl aminobenzoate, lidocaine and the like), bufferingagents such as phosphates (sodium hydrogen phosphate, sodium dihydrogenphosphate and the like), boric acid, borax, acetate (sodium acetate andthe like), carbonates (sodium carbonate, calcium carbonate, potassiumcarbonate and the like), citric acid, L-glutamate sodium and the like;pH adjusters such as sodium hydroxide, potassium hydroxide, trisodiumphosphate, sodium dihydrogen phosphate, hydrochloric acid, nitric acid,citric acid, boric acid, acetic acid and the like; preserving agentssuch as parahydroxybenzoic acid esters (propyl parahydroxybenzoate,butyl parahydroxybenzoate and the like), parabens (methylparaben,ethylparaben, propylparaben, butylparaben and the like), cationic soap(benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate,cetylpyridium chloride, and the like), alcohol derivatives(chlorobutanol, benzylalcohol, phenethylalcohol, and the like), organicacid and a salt thereof (sodium dehydroacetate, sorbic acid, sodiumsorbate, and the like), phenols (parachloromethoxyphenol,parachlorometacresol, and the like); tonicity agents such as glucose,D-sorbitol, sodium chloride, glycerin, D-mannitol, potassium chloride,concentrated glycerin, propyleneglycol, sucrose and the like; and thelike. These are sterilized in the final scheme or are prepared byasepticism. Sterile solid compositions, such as freeze-driedcomposition, may be prepared, to sterilize or to solve in steriledistilled water for injection or other sterile solvents before use.

In the present invention, cathepsin K inhibitors or types of PTH may beprovided, as well as oral formulations or injective formulations whichare prepared by normal method for manufacture, for example, in suchformulations as microencapsulation or entrapment in a gel-like sheet,for the purpose of localization or slow-action. In the formulatingprocess, pharmaceutically acceptable additives may be added. And for thepurpose of extending the serum half-life, a formulation modified bypolyethylene glycol and the like is also acceptable. Preferable arenon-invasive formulations.

As these additives, for example, a base component, a stabilizer, apreserving agent, an emulsifying agent, a coloring agent, an aromaticagent, a soothing agent, a binding agent, a buffering agent and thelike, and specifically, for example, calcium carbonate, lactose,sucrose, sorbit, mannitol, starch, amylopectin, cellulose derivatives,gelatin, cacao butter, distilled water for injection, an aqueoussolution of sodium chloride, Ringer's solution, glucose solution, humanserum albumin and the like.

When the pharmaceutical formulations are prepared in the presentinvention using these additives, the additives may be selected and usedas described in Pharmaceutical Additives Inventory (Published by MedicalJurisprudence Committee of The Pharmaceutical Manufacturer's Associationof Tokyo and Medical Jurisprudence Research Committee of OsakaPharmaceutical Manufacturer's Association). And the amount of theadditives varies depending on the dosage forms and the like if only theyare pharmaceutically acceptable.

In the present invention, types of PTH may be administered eithertopically or systemically, and particularly, when it is administeredaiming a particular bone, topical administration is excellent. Fortopical administration, intermittent administration is desirable.

In the present invention, types of PTH may be absorbed from an adhesiveformulation.

By contriving ways to administration route, it is possible to administertypes of PTH without invasion, and therefore, in the present invention,they may be administered parenterally. Examples of parenteraladministration include, subcutaneous administration, intravenousadministration, intranasal administration, pulmonary administration andthe like.

By use of a cathepsin K inhibitor in combination with a type of PTH, anadditive effect on bone densification is recognized, compared with soleadministration of a type of PTH. Preferable administration scheduleinclude, the way in which a cathepsin K inhibitor is administered orallyevery day and a type of PTH is intermittently administered. Also, whencathepsin K inhibitor is solely administered for a certain period (e.g.approximately one week, approximately one month, approximately twomonths, approximately three months, approximately 6 months,approximately one year and the like), followed by combinationadministration with PTH. And also preferable embodiment is, that atfirst types of PTH are solely administered for a certain period, andthen types of PTH are administered in combination with a cathepsin Kinhibitor. And to start dosing of a cathepsin K inhibitor and a type ofPTH is also preferable.

In addition to a cathepsin K inhibitor and a type of PTH, those agentswhich are generally used in the treatment and/or prevention of bonemetabolic diseases, for example, a calcium formulation (e.g. calciumlactate, precipitated calcium carbonate, and the like), an estrogenreceptor modulator (e.g. toremifene citrate, tamoxifen citrate,raloxifene hydrochloride, lasofoxifene tartrate, bazedoxifene acetate,PSK-3471 and the like), an androgen receptor modulator, a calcitoninformulation (e.g. salmon calcitonin (STH-32, SMC20-51), chickencalcitonin (MCI-536), secalciferol, elcatonin, TJN-135 and the like),α-calcitonin gene-related peptide formulation, ipriflavone formulations(e.g. ipriflavone and the like), an anabolic steroid formulation(nandrolone decanoate, nandrolone phenylpropionate, nandrolonecyclohexylpropionate, metenolone enanthate, mestanolone, stanozolol,oxymetholone and the like), anti-RANKL (receptor activator of NF-kappa Bligand) antibody (e.g. AMG162 and the like), PTHrP (parathyroid hormonerelated protein) (e.g. RS-66271, hPTHrP, and the like), BMP (bonemorphogenetic protein) (e.g. YM484(BMP-2) and the like), a prostaglandinreceptor agonist (e.g. EP₄ agonist (e.g. ONO-4819 and the like), EP₂agonists (e.g. ONO-8815 and the like), nitroflurbiprofen and the like),a CaR (calcium sensing receptor) antagonist, a GSK (glycogen synthasekinase) inhibitor, vitamin D (e.g. vitamin D₂ (ergocalciferol), vitaminD₃ (cholecalciferol), and the like) and their derivatives (e.g.alphacalcidol, falecalcitriol, calcitriol,1α,25-dihydroxycholecarciferol, dihydrotachysterol, ST-630, KDR, ST-630,ED-71, rocaltrol (Ro44-7190) and the like), vitamin K (e.g. vitamin K₁(phytonadione), vitamin K₂ (menatetrenone) and the like) and theirderivatives, a strontium formulation (e.g. strontium ranelate and thelike), an HMG-CoA reductase inhibitor (e.g. pravastatin, simvastatin,pitavastatin, lovastatin, rosuvastatin, atorvastatin, fluvastatin,cerivastatin and the like), a steroidal agent (e.g. KB-889 (OD14,Tibolone), Hipros (TZP-4238) and the like), a caspase-1 inhibitor (e.g.pralnacasan, nitroflurbiprofen and the like), a prostaglandin receptorantagonist, a farnesoid X receptor agonist (e.g. SR-45023A and thelike), a progesterone agonist (e.g. trimegestone and the like), an antiTNF-α antibody (e.g. infliximab, etanercept and the like), an anti IL-6antibody (e.g. MRA and the like), a female hormone formulation, anantiinflammatory drug, a metalloprotease inhibitor (e.g. minocyclinehydrochloride and the like) and the like.

Toxicity:

The compound of the present invention is very low and it is safe enoughfor medical use.

Effect of the Invention:

By use of a cathepsin K inhibitor in combination with a type of PTH, BMDis increased more efficiently than use of a type of PTH solely. Suchcombination use is useful for the prevention and/or treatment ofosteoporosis, bone fracture, arthritis, rheumatoid arthritis,osteoarthritis, hypercalcemia, osteometastasis of carcinoma,osteosarcoma, periodontal disease, bone Paget's disease and other bonemetabolic diseases. For example, by administering a cathepsin Kinhibitor orally and administering a type of PTH parenterally(subcutaneous injection, intranasal administration, and the like) theBMD of the patients suffering from bone metabolic diseases such asosteoporosis is increased efficiently.

BRIEF EXPLANATION OF FIGURES

FIG. 1 represents the BMD of the left leg tibia (4 mm slice fromproximal end) when an intermediate autopsy was performed in experiment 1(administration schedule 1).

FIG. 2 represents an osteocalcin concentration, which is a boneformation marker, when an intermediate autopsy was performed inexperiment 1 (administration schedule 1).

FIG. 3 represents a BMD of the left leg tibia (4 mm slice from proximalend) on the 83rd day in the experiment 1 (administration schedule 1).

FIG. 4 represents a concentration of bone metabolism marker (urinary CTXconcentration, serum osteocalcin concentration) on the 83rd day in theexperiment 1 (administration schedule 1).

FIG. 5 represents BMD of the tibia (4 mm slice from proximal end) on the83rd day in the experiment 2 (administration schedule 2).

FIG. 6 represents a bone metabolism marker on the 83rd day in theexperiment 2 (administration schedule 2) (urinary CTX concentration,serum osteocarcin concentration).

BEST MODE FOR CARRYING OUT THE INVENTION

The following examples illustrate the present invention, but the presentinvention is not limited to them. The solvents shown in the parenthesesof chromatography separation and TLC show the eluting or developingsolvents and the ratios are by the volume. The solvent shown in theparentheses of NMR shows the solvent used in the measurement.

In the present specification, the compounds were named by a computerprogram which carries out a nomenclature according to IUPAC rulesgenerally, i.e. ACD/Name (registered trademark, Advanced ChemistryDevelopment Inc.) or ACD/Name Batch (registered trademark, AdvancedChemistry Development Inc.), or named according to IUPAC nomenclature.

EXAMPLE 1 Preparation of(N-((1S)-3-{(2Z)-2-[(4S)-3,4-dimethyl-1,3-thiazolidin-2-ylidene]hydrazino}-2,3-dioxo-1-tetrahydro-2H-pyran-4-ylpropyl)cycloheptanecarboxamide)(compound (9))

Compound (8);(N-(3-{(2Z)-2-[(4R)-3,4-dimethyl-1,3-thiazolidin-2-ylidene]hydrazino]-2,3-dioxo-1-tetrahydro-2H-pyran-4-ylpropyl)cycloheptanecarboxamide)(1.97 g) was recrystallized from isopropanol/ethyl acetate (1/1 byvolume). From this mother liquor, the mixture of L-isomer(N-((1S)-3-{(2Z)-2-[(4S)-3,4-dimethyl-1,3-thiazolidin-2-ylidene]hydrazino}-2,3-dioxo-1-tetrahydro-2H-pyran-4-ylpropyl)cycloheptanecarboxamide)and D-isomer(N-((1R)-3-{(2Z)-2-[(4S)-3,4-dimethyl-1,3-thiazolidin-2-ylidene]hydrazino}-2,3-dioxo-1-tetrahydro-2H-pyran-4-ylpropyl)cycloheptanecarboxamide,whose D/L ratio was 32/68 (1.15 g, pale yellow powder) was obtained.

This washed with ethyl acetate, and it was allowed to stand toward roomtemperature, and the crystals were collected by filtration. The motherliquor was concentrated and the residue washed with ethyl acetate, andit was allowed to stand toward room temperature. The crystals werecollected by filtration to give a compound wherein the D/L ratio was16/84 (270 mg, pale yellow powder).

This was recrystallized from ethyl acetate to give the title compound(43 mg, white needle crystal) having the following physical data.

TLC:Rf 0.40 (methylene chloride:methanol=9:1); NMR (CDCl₃): δ 1.33 (d,J=6.22 Hz, 3H), 1.33 (m, 16H), 2.36 (m, 2H), 2.88 (dd, J=10.80, 6.04 Hz,1H), 2.98 (s, 3H), 3.36 (m, 3H), 3.85 (m, 1H), 3.95 (m, 2H), 5.15 (dd,J=9.15, 6.41 Hz, 1H), 6.45 (d, J=9.15 Hz, 1H), 8.72 (s, 1H).

Biological Examples

The effect of a cathepsin K inhibitor in combination with a type of PTHwas confirmed by the following experiments.

For the purpose of clarifying the characteristics, the effect of acathepsin K inhibitor (a bone resorption inhibitor) in combination witha type of PTH (a bone formation stimulator) was examined using anovariectomized rat osteoporosis model (abbreviated as OVX hereafter).The effect of a bisphosphonate (BP) in combination with a type of PTHwas also examined. The effects were compared with each other.

The compound (I) used as a cathepsin K inhibitor was described in theexample 8(52) of the specification of WO03/91202 and it can be preparedaccording to the method described in the specification.

Alendronate sodium hydrate (abbreviated as ALN hereafter), which wasused as a bisphosphonate (BP) was given by LKT laboratories, Inc.

As a type of PTH, human PTH (1-34) amide (APC (Lot.N05129A1); 840μg/vial), which is a partial peptide of PTH, was used.

<Method>

1) Preparation of the Solutions of the Test Compounds

-   (1) a solution of the compound (I): The compound (I) was dissolved    in 0.5% aqueous solution of methyl cellulose (MC) to give a 0.6    mg/mL solution.-   (2) a solution of ALN: ALN was dissolved in a 0.01 mol/L aqueous    solution of sodium hydroxide to give a 5.6 mg/mL solution    (approximately pH 7), and the solution was diluted with 0.5% MC    aqueous solution by 28 times, giving a 0.2 mg/mL solution.-   (3) PTH (1-34) solution: PTH (1-34) was dissolved in a saline    (10 ml) containing 0.1% bovine serum albumin (BSA) to give a 84    μg/mL solution, and at the time of use it was diluted to the    required concentration (2 μg/mL) with a saline containing 0.1% BSA.    In the following examples, PTH (1-34) is abbreviated as PTH unless    specified.    2) Test Method    Experiment 1 (Administration Schedule 1): Administration in    Combination with PTH After Repeated Administration of Bone    Resorption Inhibitor

Female retired rats (F344/NSlc) were used. At the age of 6 months, 87rats were assigned to OVX (ovariectomy) and the other 10 rats wereassigned to sham operation.

Another 15 rats were assigned to OVX and 5 rats were assigned to shamoperation, in order to these groups to an autopsy in the course.

To the 87 rats assigned to OVX, the drugs were administered according tothe grouping shown in the following table 1. To the group the compoundwas administered; a bone resorption inhibitor was administered orallyfrom the next day of OVX over a period of 83 days.

The compound (I), used as a cathepsin K inhibitor, was orallyadministered twice a day at a dose of 3 mg/kg, and ALN, used as a BP,was orally administered once a day at a dose of 1 mg/kg. On 55 daysafter OVX, the autopsy was done in autopsy group. Other groups to whichthe compound was administered, a bone resorption inhibitor wasadministered orally, and PTH or vehicle (saline containing 0.1% BSA) wasadministered subcutaneously, 55 days after OVX. When ALN wasadministered as a bone resorption inhibitor, ALN was orally administeredin the first administration, and a vehicle (0.5% MC aqueous solution)was orally administered in the second each day. The interval between thefirst and the second administration was 5-7 hours.

PTH was administered by subcutaneous injection from the back three timesa week by a dose of 10 μg/kg from the 57th day after OVX. The drugs wereadministed according to the grouping of table 1.

In the group in which the compound was administered, on the 83rd dayafter OVX, BMD of tibia, lumbar BMD, concentration of urinary C-terminaltelopeptide of type I collagen (CTX) and serum osteocalcin (OC) weremeasured. In the autopsy groups, concentration of urinary CTX and serumOC were measured on samples from the 55th day.

TABLE 1 pre-administration of a number of administration No. operationbone resorption inhibitor examples of PTH (1-34) the groups in 1 sham —10 x which the 2 OVX — 10 x (control) compound was 3 OVX — 9 10 μgadministered 4 OVX compound (I) 10 x 5 OVX ALN 10 x 6 OVX compound (I) 910 μg 7 OVX ALN 10 10 μg autopsy 8 sham — 5 groups 9 OVX — 5 10 OVXcompound (I) 5 11 OVX ALN 5Experiment 2 (Administration Schedule 2) Long Term Administration ofBone Resorption Inhibitor in Combination with a PTH

Female retired rats (F344/NSlc) were used. At the age of 6 months, 59rats were assigned to OVX and the other 10 rats were assigned to shamoperation. To the 59 rats assigned to OVX, the drugs were administeredaccording to the grouping shown in the following table 2.

To groups the compound was administered; a bone resorption inhibitor(the compound (I) (3 mg/kg, twice a day orally) as a cathepsin Kinhibitor or ALN (1 mg/kg, once a day orally) as a BP) and PTH (1-34) (3μg/kg, three times a day subcutaneously) were administered for 83 daysfrom the next day of OVX. In the groups to which PTH was notadministered, a vehicle (saline containing 0.1% BSA) subcutaneouslyinstead. When ALN was administered as a bone resorption inhibitor, ALNwas administered in the first administration and a vehicle (0.5% MCaqueous solution) was orally administered in the second administrationeach day. The interval between the first and the second administrationwas 5-7 hours.

TABLE 2 pre-administration of a number of administration No. operationbone resorption inhibitor examples of PTH (1-34) the groups in 1 sham —10 x which the 2 OVX — 10 x (control) compound was 3 OVX — 10 3 μgadministered 4 OVX compound (I) 9 x 5 OVX ALN 10 x 6 OVX compound (I) 103 μg 7 OVX ALN 10 3 μg<The Methods for the Measurement of Each Parameter>(1) The Method for the Measurement of BMD

The BMD was determined by measurement device of peripheral BMD (pQCT:peripheral Quantitative Computed Tomography, XCT-Research SA+StratecMedizintechnik GmbH, version 5.40) with voxel size 0.12 mm. The BMD ofthe left proximal tibia (at a point 4 mm from the proximal end) wasmeasured.

(2) The Method for the Measurement of Urinary CTX Concentration

Urine was collected before the day of an autopsy, and urinary CTX wasmeasured with a kit for rat CTX measurement (RatLaps ELISA;nordicbioscience). In measurement of absorbance, microplate reader(SPECTRA MAX 250, Japan Molecular Devices Inc.) was used. The measuredvalue of urinary CTX concentration (ng/mg CRE) was displayed by the CTX(ng/mL) that divided by urinary creatinine concentration (mg/mL) on thesame individual.

(3) The Method for the Measurement of Serum Osteocalsin (OC)Concentration

Fifty-five days after administration, in the autopsy, collected serumwas used to measure the serum OC concentration with a kit for OCmeasurement (BIOTRAK; Osteocalcin, rat ELISA system).

<Statistical Processing>

In order to compare the sham group and the OVX control group, t-test(EXSAS (version 6.1), ARM SYSTEX CO., LTD.); in order to compare theeffectiveness of the test compounds, Tukey test (EXSAS (version 6.1),ARM SYSTEX CO., LTD.), were used respectively. Less than 5% was assumedto be a significant difference.

<Result>

The results are shown in FIGS. 1 to 6.

Experiment 1 (Administration Schedule 1)

In order to confirm the effect of the compound (I) and ALN, 56 daysafter OVX, an intermediate autopsy was performed. In FIG. 1, bothcompounds showed an increasing effect of BMD in the tibia.

In FIG. 2, a serum OC concentration, bone formation marker, wasdecreased by the repeated administration of ALN for 55 days. Whereas aserum OC concentration was not decreased by the repeated administrationof the compound (I) for 55 days. From these results, although they areboth bone resorption inhibitors, a cathepsin K inhibitor does not affectbone formation, and it is obvious that it has a more excellent effectwhen used in combination with a type of PTH, compared with use of BP incombination with a type of PTH.

FIG. 3 shows that PTH, compound (I) and ALN suppressed the OVX-inducedBMD loss in the tibia each alone. The group in which combination withthe PTH and compound (I) showed a significant effect over PTHadministration alone. While the compound (I) showed an additive effectin BMD of tibia when used in combination with PTH, ALN did not show anyadditive effect in combination with PTH.

FIG. 4 shows that the compound (I) showed an inhibitory effecton-urinary CTX concentration both in sole administration and incombination administration with PTH. While ALN showed a urinary CTXinhibitory effect both in sole administration and in combinationadministration with PTH, the inhibitory effect was weaker than that ofcompound (I).

FIG. 4 refers to a bone formation marker. The compound (I) did notdecrease the serum OC concentration significantly by use in combinationwith PTH, over PTH sole administration. On the other hand, ALNsignificantly decreased serum OC concentration which was increased byPTH. Therefore, it was confirmed that cathepsin K inhibitors, unlikeALN, do not show an inhibitory effect on bone formation effect of PTH.

Experiment 2 (Administration Schedule 2)

A bone resorption inhibitor and PTH were administered in combination fora long term.

FIG. 5 shows that PTH, the compound (I) and ALN each inhibited thereduction of BMD of tibia caused by OVX. The effect on increase of BMDof tibia of compound (I) in combination with PTH was greater than thatof ALN in combination with PTH.

FIG. 6 shows that, the compound (I) has an inhibitory effect on urinaryCTX concentration (bone resorption marker) both in sole administrationgroup and in combination administration. However, an inhibitory effectof ALN on urinary CTX was weaker than that of compound (I).

<Discussion>

As to the increase of BMD, as a result of investigation into the effectof two types of bone resorption inhibitors (a cathepsin K inhibitor anda BP) each having different activity, about use in combination with atype of PTH (a bone formation stimulator), combination of cathepsin Kinhibitor and a type of PTH had an excellent effect in increase of BMD,over use of BP in combination with a type of PTH.

Particularly, when the bone resorption inhibitor was pre-administeredcontinually for two months, and afterwards, a bone resorption inhibitorwas used in combination with a type of PTH (experiment 1), thedifference between them proved significant. This is considered to bebecause pretreatment by BP decreased bone formation and then the effectof PTH was made to be hard to be expressed.

It was demonstrated from the experimental fact that cathepsin Kinhibitor does not inhibit bone formation but selectively inhibits boneresorption, however, BP inhibits both of them. Therefore, cathepsin Kinhibitors have an excellent effect when used in combination with PTH.

As a bone resorption inhibitor, BP does not have an excellent effectwhen used in combination with types of PTH, the present inventors havefound out that a cathepsin K inhibitor, which is also a bone resorptioninhibitor, has an excellent effect when used in combination with typesof PTH, compared with BP.

Formulation Example 1 Preparation of a Formulation Comprising 10 mg of aCathepsin K Inhibitor

The following components were admixed in a conventional method andpunched out to give 10,000 tablets each containing 10 mg of the activeingredient.

-   N-{3-[(2Z)-2-(3-methyl-1,3-thiazolidin-2-ylidene)hydrazino]-2,3-dioxo-1-tetrahydro-2H-pyran-4-ylpropyl}cycloheptanecarboxamide    hydrochloride (100 g)-   carboxymethylcellulose calcium (disintegrating agent) (20.0 g)-   magnesium stearate (lubricant) (10.0 g)-   microcrystalline cellulose (870 g)

Formulation Example 2 Preparation of a Formulation Comprising 50 mg ofPTH (1-34)

The following components were admixed in a conventional method, and thusgiven solution was sterilized by a conventional method. To each vial waspoured 5 ml of the solution to give 100 vials each containing 50 mg ofthe active ingredient.

-   PTH (1-34) (5.0 g)-   D-mannitol (5.0 g)-   distilled water (60 mL in total)

INDUSTRIAL APPLICABILITY

By use of a cathepsin K inhibitor in combination with a type of PTH, itis possible to be increased BMD more effectively, compared with use of atype of PTH solely, therefore, such combination use is useful for theprevention and/or treatment of osteoporosis, bone fracture, arthritis,rheumatoid arthritis, osteoarthritis, hypercalcemia, osteometastasis ofcarcinoma, osteosarcoma, periodontal disease, bone Paget's disease andother bone metabolic diseases.

1. A method for increasing bone mineral density, comprisingadministering to a mammal an effective amount of an agent comprising acathepsin K inhibitor and a type of PTH, wherein the cathepsin Kinhibitor is a compound of formula (W-1):

wherein R^(S) and R^(T) are each independently a hydrogen atom or a C1-4alkyl group, a salt thereof, an N-oxide thereof, a solvate thereof or aprodrug thereof; and wherein the type of PTH is human PTH (1-34).
 2. Themethod according to claim 1, wherein the agent is an agent for treatinga bone metabolic disease.
 3. The method according to claim 1, whereinthe compound of formula (W-1) is (1)N-{3-[(2Z)-2-(3-methyl-1,3-thiazolidin-2-ylidene)hydrazine]-2,3-dioxo-1-tetrahydro-2H-pyran-4-ylpropyl}cycloheptanecarboxamide, (2)N-[(1S)-3-{(2Z)-2-[(4R)-3,4-dimethyl-1,3-thiazolidin-2-ylidene]hydrazino}-2,3-dioxo-1-(tetrahydro-2H-pyran-4-yl)propyl]cycloheptanecarboxamide,(3)N-((1S)-3-{(2Z)-2-[(4S)-3-ethyl-4-methyl-1,3-thiazolidin-2-ylidene]hydrazino}-2,3-dioxo-1-tetrahydro-2H-pyran-4-ylpropyl)cycloheptanecarboxalflide,(4)N-((1R)-3-{(2Z)-2-[(4R)-3,4-dimethyl-1,3-thiazolidin-2-ylidene]hydrazino}-2,3-dioxo-1-tetrahydro-2H-pyran-4-ylpropyl)cycloheptaneCarboxamide,(5)N-(3-{(2Z)-2-[(4R)-3,4-dimethyl-1,3-thiazolidin-2-ylidene]hydrazino}-2,3-dioxo-1-tetrahydro-2H-pyran-4-ylpropyl)cycloheptanecarboxamideor (6)(N-((1S)-3-{(2Z)-2-[(4S)-3,4-dimethyl-1,3-thiazolidin-2-ylidene]hydrazino}-2,3-dioxo-1-tetrahydro-2H-pyran-4-ylpropyl)cycloheptanecarboxalmde).4. The method according to claim 3, wherein the compound of formula(W-1) is N-{3-[(2Z)-2-(3-methyl-1,3-thiazolidin-2-ylidene)hydrazine]-2,3-dioxo-1-tetrahydro-2H-pyran-4-ylpropyl}cycloheptanecarboxamideorN-[(1S)-3-{(2Z)-2-[(4R)-3,4-dimethyl-1,3-thiazolidin-2-ylidene]hydrazino}-2,3-dioxo-1-(tetrahydro-2H-pyran-4-yl)propyl]cycloheptanecarboxamide.5. The method according to claim 1, wherein the compound of formula(W-1) is orally administered and the human PTH (1-34) is parenterallyadministered.
 6. The method according to claim 1, wherein the agentfurther comprises one or more selected from a prostaglandin receptoragonist, a prostaglandin receptor antagonist, an ergocalciferol, acholecalciferol, an alphacalcidol, a falecalcitriol, a calcitriol, a1α,25-dihydroxycholecarciferol, a dihydrotachysterol, a ST-630, a KDR, aST-630, an ED-71, a rocaltrol, a calcium formulation, a phyonadione, amenatetrenone, a calcitonin formulation, a strontium formulation, anestrogen receptor modulator, anti-TNF-α antibody, anti-IL-6 antibody, anHMG-CoA reductase inhibitor, a female hormone formulation, anantiinflammatory drug, PTHrP, a bone formation protein formulation, anandrogen receptor modulator, a steroidal drug, a caspase-1 inhibitor, afarnesoid X receptor agonist, a progesteron agonist, anti-RANKLantibody, a metalloprotease inhibitor, a protein assimilation steroidalformulation, a calcium sensing receptor antagonist and a glycogensynthase kinase inhibitor.
 7. The method according to claim 2, whereinthe bone metabolic disease is osteoporosis, bone fracture, arthritis,rheumatoid arthritis, osteoarthritis, hypercalcemia, osteometastasis ofcarcinoma, osteosarcoma, periodontal disease and/or bone Paget'sdisease.